Due to the biological importance of purine and the pharmacologists' studies on purine antineoplastic and antiviral medicines, purine chemistry develops rapidly. The research shows that purine compounds have important biological activities such as anti-viral, anti-cancer, blood pressure decreasing activities. The compounds prepared by using purine derivatives as the intermediates have special efficacy on cancers, AIDS, thrombosis and the like. The medicines such as from the earliest acyclovir to the lately developed ganciclovir, valganciclovir, abacavir, fludarabine and the like are widely and clinically applied (Bioorg. Med. Chem. Lett. 2009, 19, 242-246 and Synthesis 2008, 20, 3253-3260). In WO2004/058791A2, it is disclosed that 6-(substituted) benzylamino adenosine derivatives are thought to have anticancer, mitotic, immunosuppressive and antisenescent properties. In WO2010/130233A1, it is disclosed that 2-substituted-6-(substituted)benzylamino purine riboside derivatives are thought to have antiapoptotic, anti-inflammatory and differentiation activities.
Anthony H. Ingall et al. disclosed in 1994 (WO 94/18216) N-alkyl-2-substituted ATP analogues having the following formula, and methods for preparing the same,
wherein R1 and R2 independently represent H or halogen; R3 and R4 independently represent phenyl or C1-6 alkyl optionally substituted by one or more substitute(s) selected from the group consisting of OR5, C1-6 alkylthio, NR6R7, phenyl, COOR8 and halogen; R5, R6, R7 and R8 independently represent H or C1-6 alkyl; and X represents the acidic moiety. Such PCT application further provides the representative data of the in vitro anti-platelet aggregation activity test of the compounds, in which the tests were carried out by using human platelet treated with water. Anthony H. Ingall et al. further disclosed in 1999 a process for preparing 2-alkylthio-6-(alkyl)amino-5′-substituted-9-β-D-ribofuranosyl purine compounds (AR-C compounds) having the following formula
and the results of the activity measurement of ADP-induced platelet aggregation resistance carried out by using human platelet treated with water. The results show the above compounds have the activity of ADP-induced human platelet aggregation resistance (J. Med. Chem. 1999, 42, 213-220). The AR-C compound—Canrgelor is thought to have the advantages of high activity, fast effect, short half-life, reversibility, direct inhibition of platelet activation and the like (Eur. Heart. J. Suppl. 2008, 10, 133-137 and Recent Patents on Cardiovascular Drug Discovery, 2008, 3, 194-200), and has the prospect of being developed into a new class of antithrombotics medicines. Thus studies on the activity of anti-platelet aggregation of such 5′-substituted-9-β-D-ribofuranosyl purine compounds have become one of hotspots in the field of drug research.
However, the AR-C compounds have a complex structure, a longer synthesis routes, and a very tedious post-treatment process, in particular a biochemical reagent is required for introducing a substituted triphosphoric acid side chain into the 5′-position, and the said compounds have a bad oral availability. Thus there is an urgent need to develop a candidate medicine for anti-platelet aggregation having a simple structure, easy to synthesize, a better therapeutic effect and a lower side effect.
During the studies on the platelet aggregation inhibitors, the inventor of the present invention discovered a series of novel 2-substituted hydrosulfuryl-6-substituted amino-9-β-D-ribofuranosyl purine compounds having notable activity of anti-platelet aggregation and a simple structure, and measured the in vitro anti-platelet aggregation activity of the compounds, so as to achieve the present invention.